221A Poster - 01. Cell Stress and cell death
Thursday April 07, 2:00 PM - 4:00 PM

Authors:
Sahana TG; Ke Zhang

Affiliation: Mayo Clinic, Jacksonville, FL

Keywords:
g. unfolded protein response; j. other signaling pathways

Amyotrophic Lateral Sclerosis is a neurodegenerative disease affecting upper and lower motor neurons. A GGGGCC hexanucleotide repeat expansion (HRE) in the gene C9orf72 is the most common genetic cause of ALS. Interestingly, C9orf72 mutation also causes Frontotemporal Dementia (FTD), one of the most common early-onset dementia (collectively referred to as c9ALS/FTD). The HRE generates dipeptide protein repeats (DPRs) via noncanonical translation, resulting in five different DPR species. Among these species, the arginine-rich DPRs, poly(glycine-arginine, or GR), and poly(proline-arginine, or PR) are highly toxic and play a critical role in c9ALS/FTD pathogenesis. Stress granules (SGs) are RNA-protein condensates formed in eukaryotic cells upon stress. In c9ALS/FTD, these condensates recruit several RNA binding proteins namely TDP-43, FUS, hnRNP which can potentially form solid aggregates. However, how stress granules cause neurodegeneration is incompletely understood.
In an RNAi screen in a Drosophila model of c9ALS/FTD, we identified loss of basket, the fly homolog of c-Jun N-terminal kinase (JNK) to suppress neurodegeneration. JNK is a member of the mitogen-activated protein kinase pathway (MAPK). We found that the basket/JNK activity is upregulated in fly or cell models of c9ALS/FTD via the activation of ER-stress response protein IRE1/TRAF2. Furthermore, JNK hyperactivation transactivates G3BP1, a key SG assembly factor. Our results show that JNK promotes G3BP1 expression via epigenetic modulation of histone protein 3 (H3). Moreover, IRE1 or JNK inhibitors suppress H3 modification, G3BP1 protein levels, SG assembly, and survival defects in cells expressing poly(GR) or poly(PR). Hence, our data shows a unified connection between key ALS physiologies including ER stress, JNK/MAPK activation, and SG assembly which contributes to neurodegeneration.